The experiments we propose aim to resolve two important issues in developmental neuroscience. The first is the long-standing debate as to the relative importance of mapping molecules (nature) and activity-dependent processes (nurture) toward the development of CNS connectivity. We have started to answer this question with respect to the development of topographic maps in the mouse visual system. In Aim 1, we will determine the developmental consequences on the retinocollicular map when ephrin-As, patterned neural activity, and both ephrin-As and neural activity are disrupted in vivo. We will determine how each of these mechanisms specifically acts to help form maps, the extent to which they can compensate for each other, and if topography is required to develop normal receptive field responses of target neurons. We will also compare these results with those obtained in cortical visual areas, to determine if different brain areas use these mechanisms differentially. A secondary goal of Aim 1 is to determine the mechanisms by which topographic maps align. The SC receives inputs from multiple regions of the brain, which are arranged such that they are in register with the visual world. We have designed experiments that will test the hypothesis that a combination of ephrin-As and neural activity will also be used to map and align the corticocollicular projection with that of the retinocollicular projection, but with a larger relative importance of activity-dependent mechanisms. These experiments will take advantage of our findings that EphA3-ki mice and ephrin-A2/A3/A5 tko mice have SC and V1 maps that differ in structure. Analysis of these mice will allow us to determine the extent to which the brain can adapt in structure or function to create a cohesive visual world when cortical and collicular maps have different topographic structures. Experiments proposed in Aim 2 will resolve mechanistically how topographic maps form. Multiple models for topographic mapping have been proposed and each is consistent with much of the published experimental in vivo and in vitro data. We plan to determine which, if any, of these models is true in two ways. First, we will determine the retinal vs. collicular contributions of ephrin-A5 in mapping, by removing ephrin-A5 specifically from the retina or SC, using conditional knock out technology. Second, we to determine the role of axon-axon competition in topographic map formation by analyzing the retinocollicular maps in mice that have reduced numbers of RGCs and, therefore, reduced competition for target space in the SC. PUBLIC HEALTH RELEVANCE The formation of precise neuronal connections is strictly required for productive communication between neurons. Understanding the basic processes that specify proper connectivity in the visual system will be directly relevant to treating neurological disorders involving aberrant neuronal connections and processing, such as generalized seizures, sleep disorders, and mental retardation. In addition, it is likely that the same mechanisms used to make neuronal connections during development can be manipulated in order to rewire the brain after damage due to injury or disease.